We first prepared and characterized unnatural (+)-naloxone in 1978 as an opioid receptor inert research tool useful for detecting opioid receptor mediated effects when used in conjunction with (-)-naloxone, a high affinity clinical useful narcotic antagonist. We know now that (+)-naloxone and (+)-naltrexone, long thought to be inert compounds, are functional antagonists of TLR-4 receptors and that selective acute functional antagonism of TLR4 by (+)-naloxone results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Earlier we introduced the concept of toll-like receptor (TLR)-mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation was demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. We have now examined the effect of (+)-naltrexone on cue induced heroin seeking in rats after withdrawal (incubation of heroin craving). We found that chronic administration of (+)-naltrexone decreased incubated cue-induced heroin seeking. On the other hand, acute administration of (+)-naltrexone before withdrawal day 13 did not show any effect in this test. In similar paradigms in methamphetamine trained (+)-naltrexone showed no effect.